Ca Channel Blocker
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Transcript of Ca Channel Blocker
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Calcium Channel Blocker
PHRM 304
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Stimulation Ca+2
Cell membrane
Increase cytosolic concentration of Ca+2 Also released fromsarcoplasmic
reticulum
Binding Ca+2 to a
regulatory proteinTroponin C &
Calmodulin
Uncovers myosin binding site on actin
Myosin & actin interaction results
muscle contraction
Role of Ca+2 & Ca+2 channels in muscle contraction:
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Ca2+ enters cell
Triggers
intracellularCa2+ release
Ca2+ binds to
Troponin C in
cardiac andskeletal
Calmodulin
in
vasculature
Ca2+ forms
complex
Allows actin
& myosin tointeract &
contract
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Types of calcium channel
4types of calcium channel
L type: located in skeletal, cardiac and smooch
muscles T type: found in pacemaker cells
N type: found in neurons
P type: located in purkinje cells
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Types of calcium channel
Among the Ca channels L-type calcium
channel is the target for calcium channel
blockers.
L-type consists of5 peptide subunit: 1, 2 ,,
,
1 provide central pore of the channel
Other subunits cover 1 and maintain
lipophilicity of the cell membrane.
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Fig: L-type channel
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Calcium channel blockers
Inhibition of Ca+2 flow through the channels
results in: vasodilatation and decrease cellular
response to contractile stimuli.
Sensitivity to vasodilatation action:
Coronary and
cerebral artery
Arterial
Venous
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Calcium channel blockers
Calcium channel blockers are useful in the
treatment ofhypertension and ischemic heart
disease.
Hypertension: Slows heart rate & contraction
Ischemic heart disease: Vasodilator
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CCB: Classification
Three different chemical classes
- Phenylalkylamines
- 1,4-dihydropyridines- Benzothiazepines
Second generation are more potent analogues
than first generation
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CCB: Classification
* 3rd Gen
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SAR of 1,4-dihydropyridines
N
X
HCH
3R1
R2
R3
1
2
34
5
6
General structure
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SAR of 1,4-dihydropyridines
Ester group at C3 and C5 position
Isradipine (Blocker) Activator
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Amlodipine
More
selective &
potent
Nifedipine
Only symmetrical
compound
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Chemistry
Diltiazem and verapamil are both chiral,
possessing asymmetric centers.
In each case, the dextro-rotatory ( i.e. , the
(+)-enantiomer) is approximately one order of
magnitude (10 times) more potent as a
calcium channel blocker than the levo-
rotatory (i.e., ()-enantiomer ).
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Chemistry
Amlodipine is used therapeutically as a
racemic mixture, composed of S- and R-
enantiomers, but its calcium channel-blocking
effect is confined to S-amlodipine; R-
amlodipine has 1000-fold less activity than its
S-enantiomer.
The affinity of its levorotary (-)-enantiomer tothe calcium channels is 1,000 times superior
to that of its dextrorotary (+)-enantiomer.
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Mechanism of action
Do not simply plug the hole and physically
block the channel.
Bind to a specific receptor site at 1
subunit of
L-type channel: thus inhibit Ca inflow.
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Mechanism of action
Contraction of the myocardial cells are
mediated, in part, by calcium influx.
The calcium channel blockers produce a
negative inotropic effect by interrupting the
contractile response.
The calcium channel blockers inhibit vascular
smooth muscle contraction by depriving the
cell from the calcium ions.
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Mechanism of action
Verapamil and diltiazem: ionic at physiological
pH: enter into the binding site when channel
is open.
Nifedipine (Dihydropyridines): neutral at
physiological pH-interact with Ca channel
when it is open or closed: due to its lipophillic
nature.
Verapamil
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Drug specificity
Verapamil and Diltiazem affect both the heart
and the arteriolar bed
The dihydropyridines have much less effect on
the cardiac tissues and higher specificity for
the arteriolar vascular bed.
Diltiazem
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Calcium channel blockers
Verapamil CardioselectiveSlows heart
rate &
contraction
DihydropyridinesSmooth
muscle
selective
Vasodilator
Causes reflex
tachycardia
Diltiazem IntermediateSame as
verapamil but
lesser extent
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